I think the poster you found on yahoo is confused about steroids. The two related points argued are that Sage’s effects may be mediated through cortisol-like effects and that Allopregnanolone and ganaxolone have different binding affinities at progesterone receptors. First, progesterone receptors do not mediate cortisol’s effects (so that’s a problem for this theory). Prednisone is synthetic cortisol which is only tangentially related to Allopregnanolone. Allo and cortisol share a common precursor in pregnenolone, but that is where the similarity ends. We are talking about neurosteroids here which bind on the GABA receptor (like benzodiazepines and barbiturates but differently). No one is suggesting sage’s results have anything to do with cortisol-like effects. Both of these compounds have been given to a large number of humans and no cortisol-like effects (e.g. immunosuppression and gluconeogenesis) have been reported. On the possible differences in binding, I have looked through most that has been published on Ganaxolone (about 100 papers, not that much) and I have not come accross anything that mentions significant differences in binding proerties between ganaxolone and allopregnanolone (sage 547) much less different activity at progesterone receptors. The main story here is that allo had a very short half-life (gets degraded quickly in the body) so chemists messed around with adding small groups to the allo backbone to inhibit the enzymes that broke down allo. Ganaxolone was the result. It was a success in that it inhibited the breakdown without affecting the binding properties. The result is we have a compound ganax that lasts longer and retains most/all the neuropsychological effects. The downside is that both allo and ganax still have relatively poor bioavailability (thus the large doses needed in oral studies for ganaxolone, while oral allo is so low it is a non-starter). The advance of sage-217 was that they found a modification that produced better bioavailability (reminder here that the upcoming mrns study is IV so bioavailabilty is NOT an issue). Since I did not see any papers making the point the poster is making about binding differences I am doubful that such a difference exists. At this point I think the most direct way to address the poster’s point is to ask him/her for the evidence that such a difference exists (leaving the "prednisone" issue alone as that is just wrong). I am suspicious of the motives of the post. To me it reads like concern trolling.
